Premium
Human inhibitor of growth 1 inhibits hepatoma cell growth and influences p53 stability in a variant‐dependent manner
Author(s) -
Zhu Zhi,
Luo Zhigang,
Li Yongmei,
Ni Canrong,
Li Honghua,
Zhu Minghua
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22675
Subject(s) - p14arf , ectopic expression , cell growth , microbiology and biotechnology , acetylation , cell cycle , cell cycle checkpoint , biology , cancer research , apoptosis , mdm2 , chemistry , tumor suppressor gene , cell culture , carcinogenesis , gene , biochemistry , genetics
Inhibitor of growth 1 (ING1) is a type II tumor suppressor that affects cell function by altering chromatin structure and regulating transcription. Recently, three ING1 splice variants have been cloned, but their roles in apoptosis and p53 regulation in human hepatocellular carcinoma (HCC) have not been fully elucidated. The present study found that ING1, in a variant‐dependent manner, inhibited hepatoma cell proliferation and colony formation, induced apoptosis and cell cycle arrest at G 0 /G 1 phase, and postponed tumor formation in nude mice. Expression of p33 ING1b and p24 ING1c variants, but not p47 ING1a , was markedly reduced in HCC samples. Reverse transcription polymerase chain reaction and western blotting analysis revealed that ectopic overexpression of p33 ING1b or p24 ING1c variant increased the expression of p53 downstream genes such as p21 waf1 and bax, and repressed bcl‐2 expression ( P < 0.01), whereas p47 ING1a inactivated p21 waf1 promoter ( P < 0.01). Furthermore, we found that p33 ING1b and p24 ING1c repressed Mdm2 expression ( P < 0.01) and competed with Mdm2 for binding to p53. Interestingly, p33 ING1b and p24 ING1c did not directly bind to Mdm2 protein but strongly increased p14 arf expression ( P < 0.01) and interacted with p14 arf protein to stimulate p53. Moreover, we found that ectopic overexpression of p33 ING1b or p24 ING1c significantly induced p53 protein acetylation at Lys‐373/Lys‐382 residue, but did not alter the phosphorylation status of p53. Conclusion: ING1 variants p33 ING1b and p24 ING1c may modulate p53 activity and subsequently inhibit hepatoma cell growth by at least two possible mechanisms: interacting with Mdm2 and p14 arf to stabilize and activate p53, or increasing p53 acetylation. (H EPATOLOGY 2009.)